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Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.

Felts AS, Siegel BS, Young SM, Moth CW, Lybrand TP, Dannenberg AJ, Marnett LJ, Subbaramaiah K - J. Med. Chem. (2008)

Bottom Line: Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity.Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes.Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

ABSTRACT
A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 microM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARgamma was demonstrated by the displacement of [(3)H]troglitazone, a PPARgamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes. Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

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Compound 24 activates adipogenesis in 3T3-L1 cells. Images of Oil Red O stained 3T3-L1 cells were taken after treatment with (a) vehicle (b) 1 μM troglitazone or (c) 1 μM 24 for 48 h (200×).
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fig6: Compound 24 activates adipogenesis in 3T3-L1 cells. Images of Oil Red O stained 3T3-L1 cells were taken after treatment with (a) vehicle (b) 1 μM troglitazone or (c) 1 μM 24 for 48 h (200×).

Mentions: To further evaluate the functional significance of 24 as a PPARγ agonist, we investigated its effects on the levels of L-FABP and aP2, two established PPARγ target genes.20,21 Cells were treated with 0−1 μM 24 for 24 h. Following treatment, cell lysates were prepared and Western blotting was performed. Compound 24 induced both L-FABP and aP2 (Figure 4a) over the same concentration range that stimulated PPARγ binding (Figure 3). Induction of L-FABP and aP2 was suppressed by pretreatment with 30 (GW9662)(22) (Figure 5), a PPARγ antagonist (Figure 4b). PPARγ agonists induce adipogenesis;(23) hence, we also investigated whether 24 could stimulate triglyceride accumulation in 3T3-L1 cells, a murine fibroblast cell line. As shown in Figure 6, staining with Oil Red O revealed formation of lipid droplets in cells treated with 24 in a manner similar to the known PPARγ activator, troglitazone.


Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.

Felts AS, Siegel BS, Young SM, Moth CW, Lybrand TP, Dannenberg AJ, Marnett LJ, Subbaramaiah K - J. Med. Chem. (2008)

Compound 24 activates adipogenesis in 3T3-L1 cells. Images of Oil Red O stained 3T3-L1 cells were taken after treatment with (a) vehicle (b) 1 μM troglitazone or (c) 1 μM 24 for 48 h (200×).
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651753&req=5

fig6: Compound 24 activates adipogenesis in 3T3-L1 cells. Images of Oil Red O stained 3T3-L1 cells were taken after treatment with (a) vehicle (b) 1 μM troglitazone or (c) 1 μM 24 for 48 h (200×).
Mentions: To further evaluate the functional significance of 24 as a PPARγ agonist, we investigated its effects on the levels of L-FABP and aP2, two established PPARγ target genes.20,21 Cells were treated with 0−1 μM 24 for 24 h. Following treatment, cell lysates were prepared and Western blotting was performed. Compound 24 induced both L-FABP and aP2 (Figure 4a) over the same concentration range that stimulated PPARγ binding (Figure 3). Induction of L-FABP and aP2 was suppressed by pretreatment with 30 (GW9662)(22) (Figure 5), a PPARγ antagonist (Figure 4b). PPARγ agonists induce adipogenesis;(23) hence, we also investigated whether 24 could stimulate triglyceride accumulation in 3T3-L1 cells, a murine fibroblast cell line. As shown in Figure 6, staining with Oil Red O revealed formation of lipid droplets in cells treated with 24 in a manner similar to the known PPARγ activator, troglitazone.

Bottom Line: Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity.Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes.Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

ABSTRACT
A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 microM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARgamma was demonstrated by the displacement of [(3)H]troglitazone, a PPARgamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes. Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

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